A biomarker model of the progression of Alzheimer's disease is supported by a clinical study of people with mild cognitive impairment, researchers reported.

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A biomarker model of the progression of Alzheimer's disease is supported by a clinical study of people with mild cognitive impairment (MCI).

Point out that among patients with MCI in the group with no biomarkers, only one of 22 patients progressed during the study.

A biomarker model of the progression of Alzheimer's disease is supported by a clinical study of people with mild cognitive impairment (MCI), researchers reported.

In a multicenter prospective study, only one patient with none of the multiple biomarkers of Alzheimer's disease neuropathology progressed to dementia, according to Giovanni Frisoni, MD, of IRCCS Fatebenefratelli in Brescia, Italy, and colleagues.

But all patients with all biomarkers progressed, Frisoni and colleagues reported online in Neurology.

On the other hand, 26% of the 73 patients did not fit the 2011 model, which proposed that biomarkers of amyloidosis -- abnormal tracer retention on amyloid PET imaging and low Aβ42 concentration in the cerebral spinal fluid -- should become abnormal earlier in the disease course, followed by biomarkers of synaptic dysfunction (cortical hypometabolism on FDG-PET studies), and finally by loss of volume in the hippocampus (brain atrophy on structural MRI).

To study the clinical validity of the model, Frisoni and colleagues enrolled patients with MCI in three centers, measured the appropriate biomarkers, including Aβ42 concentration in cerebral spinal fluid), and followed them over time.

They found that 22 patients had none of the markers, 11 had just abnormal beta-amyloid, 11 had abnormal beta-amyloid and markers of synaptic dysfunction, and 10 had all three markers.

A fifth group of 19 patients did not fit the model: four had both abnormal beta-amyloid and loss of hippocampal volume, but no indication of synaptic dysfunction, while the remaining 15 had no beta-amyloid abnormality but had one or both of the other two markers.

Of the 73 patients, 44 had stable MCI and had no significant change in cognition over an average of 31.8 months of follow-up. The other 29 were classified as having progressive disease and saw an average decline of 4.6 points on the mini-mental state examination over an average of 23.2 months of follow-up.

In the group with no biomarkers, only one of 22 patients progressed during the study, compared with all of those who had all biomarkers, Frisoni and colleagues reported.

The rates of progression were intermediate in the other groups -- three of 11 in the one-marker group and seven of 11 in the two-marker group -- and the trend was statistically significant (P<0.0001).

Among the 19 patients in the fifth group, eight had progressive MCI, the authors reported.

The pattern is "in line" with the current Alzheimer's model, in that absence of the biomarkers, or presence of all of them, is "associated with exceptional and universal development of dementia," respectively, they said.

The unusual cases in the fifth group might be due either to atypical neurobiology or to inaccurate thresholds for biomarker abnormality, Frisoni and colleagues added.

They cautioned that the study was small and of short duration, so that results might be different with larger and longer analyses.

Indeed, the findings "represent the first chapter of a longer work," commented David Knopman, MD, of the Mayo Clinic in Rochester, Minn., in an accompanying editorial.

Knopman, who is also deputy editor of the journal, argued that Alzheimer's biomarkers "are going to change how the disease is viewed."

But "much more work remains to determine their optimal use and bring them into routine clinical practice," he concluded.

The study had support from the Swedish Research Council, the Strategic Research Program in Neuroscience at Karolinska Institutet, Swedish Brain Power, and the Italian Ministry of Health.

The journal said the researchers reported no relevant financial conflicts of interest.

The editorial had support from the NIH and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation. Knopman is deputy editor for Neurology and reported financial links with Lilly Pharmaceuticals, TauRx Pharmaceuticals, and Allon Pharmaceuticals.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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